In one embodiment, the invention provides an enantioselective method for preparing compounds having Formula (S1), (S2), or (S3) as follows: 
wherein
R1 is independently an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; and
R2, R3, R4, R5, R6 and R7 are, independently, hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy.
Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group.
The term xe2x80x9coptionally substituted alkylxe2x80x9d refers to unsubstituted or substituted straight or branched chain hydrocarbon groups having 1-20 carbon atoms, preferably 1-7 carbon atoms. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halo, hydroxy, cycloalkyl, alkoxy, alkenyl, alkynyl, alkylthio, alkylthiono, sulfonyl, nitro, cyano, alkoxycarbonyl, aryl, aralkoxy, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like.
The term xe2x80x9clower alkylxe2x80x9d refers to those alkyl groups as described above having 1-7 carbon atoms, preferably 1-4 carbon atoms.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to fluorine, chlorine, bromine and iodine.
The term xe2x80x9calkenylxe2x80x9d refers to any of the above alkyl groups having at least two carbon atoms and further containing at least one carbon to carbon double bond at the attachment point. Groups having 2-4 carbon atoms are preferred.
The term xe2x80x9calkynylxe2x80x9d refers to any of the above alkyl groups having at least two carbon atoms and further containing at least one carbon to carbon triple bond at the attachment point. Groups having 2-4 carbon atoms are preferred.
The term xe2x80x9ccycloalkylxe2x80x9d refers to optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each of which may be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkylthio, nitro, cyano, alkoxycarbonyl, sulfonyl, heterocyclyl and the like.
Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like.
Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to alkyl-Oxe2x80x94.
The term xe2x80x9calkylthioxe2x80x9d refers to alkyl-Sxe2x80x94.
The term xe2x80x9calkylthionoxe2x80x9d refers to alkyl-S(O)xe2x80x94.
The term xe2x80x9ctrialkylsilylxe2x80x9d refers to (alkyl)3Sixe2x80x94.
The term xe2x80x9ctrialkylsilyloxyxe2x80x9d refers to (alkyl)3SiOxe2x80x94.
The term xe2x80x9calkylsulfonylxe2x80x9d refers to alkyl-S(O)2xe2x80x94.
The term xe2x80x9csulfonylxe2x80x9d refers to alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-12 carbon atoms in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups, each of which may optionally be substituted by 1-4 substituents, such as alkyl, halo, hydroxy, alkoxy, acyl, thiol, alkylthio, nitro, cyano, sulfonyl, heterocyclyl and the like.
The term xe2x80x9cmonocyclic arylxe2x80x9d refers to optionally substituted phenyl as described under aryl.
The term xe2x80x9caralkylxe2x80x9d refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term xe2x80x9caralkylthioxe2x80x9d refers to aralkyl-Sxe2x80x94.
The term xe2x80x9caralkoxyxe2x80x9d refers to an aryl group bonded directly through an alkoxy group.
The term xe2x80x9carylsulfonylxe2x80x9d refers to aryl-S(O)2xe2x80x94.
The term xe2x80x9carylthioxe2x80x9d refers to aryl-Sxe2x80x94.
The term xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocycloxe2x80x9d refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The heterocyclic group may be attached at a heteroatom or a carbon atom.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic heterocycle, e.g., monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl and the like, optionally substituted by, e.g., lower alkyl, lower alkoxy or halo.
The term xe2x80x9cheteroarylsulfonylxe2x80x9d refers to heteroaryl-S(O)2xe2x80x94.
The term xe2x80x9cheteroaralkylxe2x80x9d refers to a heteroaryl group bonded through an alkyl group.
Accordingly, compounds having Formula (S1), (S2), or (S3) may be prepared by first condensing a disilyloxydiene having Formula (II) 
wherein
R1 is independently an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; and
R and Rxe2x80x2 represent lower alkyl, preferably ethyl or methyl, and R and Rxe2x80x2 may be identical or different,
with an aldehyde having Formula (Q1), (Q2), or (Q3) as follows: 
wherein R2, R3, R4, R5, R6 and R7 have meanings as defined for Formula (S1), (S2), or (S3) in the presence of a titanium (IV) catalyst having Formula (IV) 
wherein R8 is a lower alkyl, and the binaphthyl moiety is in the S-configuration, in an inert solvent to obtain compounds having Formula (S1), (S2), or (S3) in high chemical yield and enantiomeric purity.
In the aldol condensation above the molar ratio of a disilyloxydiene of Formula (II) to an aldehyde having Formula (Q1), (Q2), or (Q3) initially present in the reaction mixture ranges from 1:1 to 6:1, preferably from 1:1 to 4:1, and more preferably from 1.5:1 to 3:1.
The disilyloxydiene of Formula (II) may be prepared by reacting an acetoacetate of Formula (VI) 
wherein R1 is independently an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; with a silylating agent, such as tri(lower alkyl)silyl chloride or tri(lower alkyl)silyl trifluoromethanesulfonate, preferably trimethylsilyl chloride or triethylsilyl chloride, in the presence of a base, such as triethylamine, diisopropylethylamine or N-methylmorpholine, preferably triethylamine, in an organic solvent, such as pentane, hexane, heptane, tetrahydrofuran, diethyl ether or dichloromethane, preferably hexane, at a temperature ranging from about xe2x88x9225xc2x0 C. to about 30xc2x0 C. to form a silylenolether of Formula (VII) 
wherein
R1 is independently an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; and
R is a lower alkyl.
The silylenolether of Formula (VII) may then be treated with a base, such as lithium diisopropylamide or lithium, sodium or potassium bis(trimethylsilyl)amide, preferably lithium diisopropylamide, followed by addition of a silylating agent, such as tri(lower alkyl)silyl chloride or tri(lower alkyl)silyl trifluoromethanesulfonate, preferably trimethylsilyl chloride or triethylsilyl chloride, in an inert solvent, such as diethylether or tetrahydrofuran, preferably tetrahydrofuran, at a temperature ranging from about xe2x88x9240xc2x0 C. to about xe2x88x92100xc2x0 C. to form the disilyloxydiene of Formula (II).
Lithium diisopropylamide may be generated in situ from diisopropylamine and n-butyllithium under conditions well-known in the art or as illustrated in the examples herein.
The molar ratio of the titanium (IV) catalyst of Formula (IV) to an aldehyde of Formula (Q1), (Q2), or (Q3) initially present in the aldol condensation above ranges from 0.01:1 to 0.15:1, preferably from 0.04:1 to 0.1:1.
The titanium (IV) catalyst of Formula (IV) may be prepared in situ by reacting Ti(OR8)4, in which R8 is lower alkyl, preferably isopropyl, with (S)-2,2xe2x80x2-binaphthol of the Formula (VIII) 
(S)-2,2xe2x80x2-Binaphthol of Formula (VIII) is commercially available, e.g., from Karlshamns under the trademark BINOL, and titanium (IV) tetra-alkoxides, preferably titanium (IV) tetraisopropoxide, may optionally be generated in situ from titanium tetrachloride and sodium or lithium alkoxide, preferably sodium or lithium isopropoxide.
The aldol condensation above may be carried out in a polar aprotic solvent, such as tetrahydrofuran, diethylether or dimethoxyethane, preferably tetrahydrofuran. A combination of solvents may also be used. The reaction temperature may range from about 0xc2x0 C. to about 70xc2x0 C., preferably from about 10xc2x0 C. to about 60xc2x0 C., and more preferably from about 15xc2x0 C. to about 55xc2x0 C. The reaction is conducted for a period of time from about 1 hour to about 72 hours, preferably from about 2 hours to about 24 hours.
The compounds having Formula (S1), (S2), or (S3) may optionally be purified by physical or chemical means to enrich the enantiomeric purity. Examples of such means for enrichment include, but are not limited to, crystallization and chiral preparative chromatography, such as high pressure liquid chromatography (HPLC).
In another embodiment, the invention provides a stereoselective method for the preparation of syn-3(R),5(S)-dihydroxyesters by reducing compounds of Formula (S1), (S2), or (S3). The syn-3(R),5(S)-dihydroxyesters have Formula (V1), (V2), or (V3) as follows: 
wherein
R1 is, independently, an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; and
R2, R3, R4, R5, R6 and R7 are, independently, hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy.
The stereoselective reduction of compounds having Formula (S1), (S2), or (S3) may be achieved in the presence of a di(lower alkyl)methoxyborane, such as diethylmethoxyborane or dibutylmethoxyborane, preferably diethylmethoxyborane, in a polar solvent, such as tetrahydrofuran or lower alcohol, e.g., methanol or ethanol, or a mixture of solvents thereof, preferably a mixture of tetrahydrofuran and methanol. The reducing agent used in the reduction step above may be selected from a group of hydride reagents, such as sodium and lithium borohydride. Preferably the reducing agent is sodium borohydride. The reaction may be conducted at a temperature ranging from about xe2x88x9220xc2x0 C. to about xe2x88x92100xc2x0 C., preferably from about xe2x88x9250xc2x0 C. to about xe2x88x9280xc2x0 C.
In another embodiment, the invention provides methods for the preparation of calcium salts having Formula (W1), (W2), or (W3) as follows: 
wherein R2, R3, R4, R5, R6 and R7 are, independently, hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy.
Calcium salts of Formula (W1), (W2), or (W3) may be prepared by first hydrolyzing compounds of Formula (V1), (V2), or (V3) in the presence of an aqueous base to form the corresponding alkali metal salts having Formula (X1), (X2), or (X3) as follows: 
wherein R2, R3, R4, R5, R6 and R7 are, independently, hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy; and M is sodium, lithium or potassium, preferably sodium.
The hydrolysis step above may be carried out in an organic solvent, such as a lower alcohol, preferably ethanol, and the base used in said hydrolysis is preferably selected from aqueous potassium hydroxide, aqueous lithium hydroxide and aqueous sodium hydroxide. More preferably, the base is sodium hydroxide. The hydrolysis is preferably conducted at a temperature ranging from about xe2x88x9210xc2x0 C. to about 30xc2x0 C., preferably from about 0xc2x0 C. to about 25xc2x0 C.
Alkali metal salts having Formula (X1), (X2), or (X3) may then be converted to corresponding calcium salts of Formula (W1), (W2), or (W3), by reacting an aqueous solution of an alkali metal salt of Formula (X1), (X2), or (X3) with an aqueous solution of a suitable calcium source at an ambient temperature, preferably at room temperature. Suitable calcium sources include, but are not limited to, calcium chloride, calcium oxide and calcium hydroxide.
Alternatively, calcium salts of Formula (W1), (W2), or (W3) may be obtained by first cyclizing compounds of Formula (V1), (V2), or (V3) in the presence of an acid and an aprotic water-miscible solvent to form the corresponding lactone having Formula (Y1), (Y2), or (Y3) as follows: 
and acid addition salts thereof;
wherein R2, R3, R4, R5, R6 and R7 are, independently, hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy.
The cyclization above may be carried out in the presence of an acid, such as trifluoroacetic acid or a strong mineral acid, preferably concentrated hydrochloric acid, in an aprotic water-miscible solvent such tetrahydrofuran or acetonitrile, preferably acetonitrile, at a temperature ranging from 0-25xc2x0 C. Lactones of Formula (Y1), (Y2), or (Y3), and acid addition salts thereof, preferably hydrochloric acid salts thereof, may contain small amounts of the unreacted starting material of Formula (V1), (V2), or (V3); and the corresponding acid having Formula (Z1), (Z2), or (Z3) as follows: 
and acid addition salts thereof, preferably hydrochloric acid salts thereof;
wherein R2, R3, R4, R5, R6 and R7 are, independently, hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy.
Lactones of Formula (Y1) (Y2), or (Y3), contaminants thereof, and acid addition salts thereof, may then be converted to the corresponding calcium salts of Formula (W1), (W2), or (W3) analogously as described herein above for compounds of Formula (V1), (V2), or (V3), or modifications thereof.
In one embodiment of the invention, the calcium salt is pitavastatin calcium.
The processes described herein above are conducted under inert atmosphere, preferably under nitrogen atmosphere. It is within the scope of the invention to use a molecular sieves during the preparation of the compounds of the invention, especially in the step of condensing a disilyloxydiene with an aldehyde of Formula (Q1), (Q2), or (Q3), in the presence of a titanium (IV) catalyst. Water may optionally be added to the molecular sieves prior to using the molecular sieves. In one embodiment, the water content of the molecular sieves is preferably from about 1 wt % to about 15 wt %.
The type of reactor used to prepare the compounds of the invention include batch, continuous, and semicontinuous reactors. It is within the scope of the invention to prepare the compounds in an external recycle reactor which allows: (i) in-situ pre-treatment or post-treatment of the solid mol sieves molecular sieves (ii) elimination of molecular sieves filtration at the end of the reaction and (iii) easy re-use of the molecular sieves for possible multicycle operation.
In starting compounds and intermediates, which are converted to the compounds of the invention in a manner described herein, functional groups present, such as amino, thiol, carboxyl and hydroxy groups, are optionally protected by conventional protecting groups that are common in preparative organic chemistry. Protected amino, thiol, carboxyl and hydroxyl groups are those that can be converted under mild conditions into free amino thiol, carboxyl and hydroxyl groups without the molecular framework being destroyed or other undesired side reactions taking place.
The purpose of introducing protecting groups is to protect the functional groups from undesired reactions with reaction components under the conditions used for carrying out a desired chemical transformation. The need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxyl group, amino group, etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions. Well-known protecting groups that meet these conditions and their introduction and removal are described, e.g., in McOmie, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Plenum Press, London, N.Y. (1973); and Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Wiley, N.Y. (1991).
The compounds of the invention may be prepared in high enantiomeric purity, and therefor, eliminate the need for resolution. As used herein, high enantiomeric purity or enantioselectivity means at least 70% optical purity, preferably at least 80% optical purity, most preferably at least 97% optical purity.
The compounds of the invention are especially useful for treating or preventing atherosclerosis. In one embodiment of the invention, the compounds inhibit the enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase which has been identified as a rate-limiting enzyme in the cholesterol biosynthetic pathway.
The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centrigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 and 100 mmHg (=20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis, melting point (mp) and spectroscopic characteristics, e.g., MS, IR and NMR. Abbreviations used are those conventional in the art.